Congenic fine-mapping identifies a major causal locus for variation in the native collateral circulation and ischemic injury in brain and lower extremity.

Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE

Publication: Baltimore, MD : Lippincott Williams & Wilkins
Original Publication: Baltimore, Md. Grune & Stratton.

Brain/*blood supply ; Chromosome Mapping/*methods ; Collateral Circulation/*genetics ; Hindlimb/*blood supply ; Infarction, Middle Cerebral Artery/*genetics ; Ischemia/*genetics; Animals ; Disease Models, Animal ; Female ; Genomics/methods ; Haplotypes ; Heterozygote ; Infarction, Middle Cerebral Artery/physiopathology ; Ischemia/physiopathology ; Male ; Mice ; Mice, Congenic ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Quantitative Trait Loci

Rationale: Severity of tissue injury in occlusive disease is dependent on the extent (number and diameter) of collateral vessels, which varies widely among healthy mice and humans. However, the causative genetic elements are unknown. Recently, much of the variation among different mouse strains, including C57Bl/6J (B6, high extent) and BALB/cByJ (Bc, low extent), was linked to a quantitative trait locus on chromosome 7 (Candq1).
Objective: We used congenic mapping to refine Candq1 and its candidate genes to create an isogenic strain set with large differences in collateral extent to assess their impact and the impact of Candq1, alone, on ischemic injury.
Methods and Results: Six congenic strains possessing portions of Candq1 introgressed from B6 into Bc were generated and phenotyped. Candq1 was refined from 27 to 0.737 Mb with full retention of effect, that is, return or rescue of phenotypes from the poor values in Bc to nearly those of wild-type B6 in the B6/B6 congenic mice as follows: 83% rescue of low pial collateral extent and 4.5-fold increase in blood flow and 85% reduction of infarct volume after middle cerebral artery occlusion; 54% rescue of low skeletal muscle collaterals and augmented recovery of perfusion (83%) and function after femoral artery ligation. Gene deletion and in silico analysis further delineated the candidate genes.
Conclusions: We have significantly refined Candq1 (now designated determinant of collateral extent 1; Dce1), demonstrated that genetic background-dependent variation in collaterals is a major factor underlying differences in ischemic tissue injury, and generated a congenic strain set with wide allele dose-dependent variation in collateral extent for use in investigations of the collateral circulation.

Comment in: Circ Res. 2014 Feb 14;114(4):591-3. (PMID: 24526671)

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NS083633 United States NS NINDS NIH HHS; R01 NS083633 United States NS NINDS NIH HHS; HL090655 United States HL NHLBI NIH HHS; R01 HL090655 United States HL NHLBI NIH HHS; R01 HL111070 United States HL NHLBI NIH HHS; HL111073 United States HL NHLBI NIH HHS

Keywords: collateral circulation; genetics; models, animal; peripheral vascular diseases

Date Created: 20131205 Date Completed: 20140421 Latest Revision: 20211021

20230127

PMC3966023

10.1161/CIRCRESAHA.114.302931

24300334